Dataset Information

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid ? production and clearance.

ABSTRACT:

Aim

Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/A? pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.

Methods

Cell-based assays for screening anti-amyloid compounds were established by assessing A? accumulation in HEK293-APP_sw and CHO-APP cells, and A? clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg^-1·d^-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate A? and sAPP? levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.

Results

LX2343 (5-20 ?mol/L) dose-dependently decreased A? accumulation in HEK293-APP_sw and CHO-APP cells, and promoted A? clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APP^Thr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC₅₀ value of 11.43±0.36 ?mol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing A? clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the A? pathology in their brains.

Conclusion

LX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both A? production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.

SUBMITTER: Guo XD

PROVIDER: S-EPMC5057240 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Publications

Small molecule LX2343 ameliorates cognitive deficits in AD model mice by targeting both amyloid β production and clearance.

Guo Xiao-Dan XD Sun Guang-Long GL Zhou Ting-Ting TT Xu Xin X Zhu Zhi-Yuan ZY Rukachaisirikul Vatcharin V Hu Li-Hong LH Shen Xu X

Acta pharmacologica Sinica 20160829 10

<h4>Aim</h4>Streptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/Aβ pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(p ...[more]

PMID: 27569389

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Project description:BackgroundAmyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied.MethodsTo genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).ResultsIt is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aβ production in the perforant path and levels of soluble Aβ and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and β-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway.ConclusionsOur findings demonstrate that perforant path NgR plays an important role in regulating APP/Aβ level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.